Ionosonic drug delivery apparatus

ABSTRACT

An improved apparatus for the iontophoretic-ultrasonic (ionosonic) transdermal delivery of medication across the skin or other biological membrane so the medication can be absorbed by the adjacent tissues and blood vessels. The apparatus can be adapted for large dermal area application or for a smaller area of application, depending on the choice of specific electrode employed. The apparatus comprises a multichannel iontophoretic applicator electrode. Multiple piezoelectric elements are mounted on the ionotophoetic electrode. The combination of ultrasonic vibration and iontophoresis creates a significant improvement in the penetration of medicament in contact with the skin or mucous membrane underlying the electrode. Drug delivery systems employing biofeedback such as the transcutaneous delivery of insulin based on tissue glucose are outlined based on this ionosonic technology.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 08/044,586; filed Apr. 7,1993 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the transdermal delivery ofmedicament and, more specifically, to an apparatus for the iontophoreticand ultrasonic delivery of medication across the skin or otherbiological tissue.

2. Prior Art

Iontophoresis has existed for several centuries as a means for applyingmedication locally through a patient's skin and for deliveringmedicaments to the eyes and ears. The application of an electric fieldto the skin is known to greatly enhance the skin's permeability tovarious ionic agents. The use of iontophoretic techniques has obviatedthe need for hypodermic injection of certain medicaments, therebyeliminating the concomitant problems of trauma, pain and risk ofinfection to the patient.

Iontophoresis involves the application of an electromotive force todrive or repel oppositely charged ions through the dermal layers intothe area to be treated; either into the surrounding tissues forlocalized treatment or into the circulatory system for systemictreatment. Positively charged ions are driven into the skin at the anodewhile negatively charged ions are driven into the skin at the cathode.Studies have shown increased skin penetration of drugs at anodic orcathodic electrodes regardless of the predominant molecular ioniccharge. This effect is mediated by polarization and osmotic effects.Regardless of the electrical charge on the medicament employed, twoelectrodes are used in conjunction with the patient's skin to form aclosed circuit to promote the penetration or absorption of themedicament through the skin underlying the working electrode.

One readily observed benefit of transdermal iontophoretic drug deliveryis the increased efficacy of the drugs delivered in this fashion. U.S.Pat. No. 5,160,316, to the instant inventor, incorporated herein byreference, describes the use of a multichannel dispersive electrode.Each channel is driven by separate electronic circuits to assure widedispersion and enhanced penetration of medicament. Such wide fieldelectrodes not only can cover a wide area of body without succumbing to"tunneling effects" but provide sufficient skin penetration to functionas a systemic drug delivery system. A co-pending patent application bythe present inventor describes a user-friendly iontophoretic system todeliver nicotine as a device to help people quit smoking or,alternatively, to provide established smokers with a noncarcinogenicsmokeless cigarette.

Prior art iontophoretic systems have not proved useful for delivery ofinsulin via the transdermal route. Such a system would be extremelyimportant in the management of diabetic patients and in decreasing thelong term complications of diabetes. The patient would be freed frommultiple injections of insulin and strict dietary controls which are themainstay of current therapy of Diabetes Mellitus. It is believed thatimproved control of intraday glucose fluctuations will significantlydecrease the long term complications of diabetes such as blindness andrenal failure. Improved control of diabetic pregnancy and children willenhance and prolong life. An iontophoretic insulin delivery system mustemploy an electrode that avoids current flowing along the path of leastresistance into a lesion or skin rupture, resulting in a localized burn.

The foregoing problems are solved by the present invention by providingan improved iontophoretic medicament applicator and combining thisiontophoretic dispersion electrode with ultrasonic enhancement ofpenetration. Ultrasonic fields can readily be generated in the skinunderlying an electrode by means of oscillator circuits applying a highfrequency voltage waveform to piezoelectric crystals (i.e. quartz)mounted on the dispersive application electrode. It is the nature ofpiezoelectric crystals to convert electrical oscillations to vibrationby means of crystal lattice elongation. Numerous materials such asceramics (barium titanate), and variations of lead zicornate-leadtitanate exhibit good piezoelectric properties and can be mounted onsuch an electrode. A preferred manufacture of a pliant contouringelectrode producing low energy ultrasonic fields utilizes a sheet ofKynar™ polyvinelidene fluoride film that exhibits piezoelectricproperties when energized yet retains pliability, stability and absenceof toxicity. Such laminates of piezo film are known in the art and havealready been manufactured. A bending motion (analogous to bimetallicaction of thermostats) can be generated in response to an appliedvoltage where the top film expands while the bottom contracts.Alternating voltage creates film vibration in phase with appliedoscillator output. For higher energy applications multiple mountedpiezoelectric crystals or ceramic elements on a flexible iontophoreticsheet will be preferable.

SUMMARY OF THE INVENTION

Surprisingly, the instant inventor has discovered that combining amultichannel iontophoretic electrode with ultrasonic enhancement greatlyimproves transdermal penetration of larger molecules such as insulin orother peptide. Ultrasound applied to the skin has been shown to enhanceskin penetration by (a) disrupting the protective keratin layer; and (b)forming micro-droplets that can readily be charged. A transdermaldelivery system combining ultrasound and iontophoresis may be adapted toincorporate percutaneous infrared based glucose sensor technology withthe ultrasonic-iontophoretic driver electrode in a biofeedbackconfiguration. Such a system can be worn by a suffering diabetic. Thesensor monitors the tissue glucose level, and if it exceeds a specifiedlevel the unit will begin to drive insulin through the skin until anormal glucose level is reestablished.

The improved iontophoretic applicator may also be suitable for treatmentof large areas of skin where the ultrasonic component of the medicamentdriver electrode will further enhance the penetration of substances likeantibiotic, antifungal, or growth factors when driven into a burn escharto promote healing and minimize infection.

It is, therefore, a primary object of this invention to describe theconstruction of a driver electrode that combines the multichanneliontophoretic electrode with piezoelectric ultrasonic applicationelements into a combined structure which when linked withelectrophoretic and ultrasonic driver circuits create a system forgreatly enhanced skin penetration of medications, hormones, peptide andother therapeutic substances.

It is an additional object of the present invention to provide animproved iontophoretic medicament applicator that can be used to treat alarge dermal area.

It is another object of the present invention to provide a moreefficient iontophoretic medicament applicator by coupling theiontophoretic applicator electrode with piezoelectric ultrasonicelements at the site of iontophoretic application.

It is still another object of the present invention to provide animproved iontophoretic medicament applicator that is driven by reusablecircuit and ultrasonic sources and comprises a disposable skincontacting surface that contains an iontophoretic dispersion electrodeopen cell medicament reservoir in contact with the skin surface.

It is a feature of the present invention that the iontophoreticmedicament applicator for large dermal areas employs a multichannelelectrodispersive matrix to drive the ionic medicament from the matrixor pad into the skin area.

It is another feature of the present invention that the iontophoreticmedicament applicator for large dermal areas employs a carrier matrixwith the medicament dispersed therewithin in combination with anadhesive layer to facilitate fastening to the patient's skin.

It is a further feature of the present invention that the iontophoreticmedicament applicator for large dermal areas employs a conductive matrixand a carrier matrix with the medicament dispersed therewithin and whichare sufficiently flexible to conform to the contours of the body areabeing treated.

It is still another object of the present invention to provide adisposable iontophoretic medicament applicator which employs anabsorbent, inert material that is non-corrosive to contain themedicament or therapeutic agent.

It is yet another feature of the present invention that the disposableiontophoretic medicament applicator and the neutral electrode array andactive electrode array are integrated into a single band type device tobe worn about an extremity providing for comfort and electrical contactwith skin. The ultrasonic crystal sources are preferably within closeproximity to the dispersive iontophoretic electrodes while the powersource and control circuitry for the ultrasonic drivers and the currentlimited drivers for the iontophoretic components are mounted on aband-type device as a control structure similar to that of a largewatch.

It is yet another feature of the present invention that it provide aneedleless transcutaneous drug delivery system in which the multichanneliontophoretic dispersion electrode together with the ultrasonic elementscan comprise a flexible sheet with remote power and control circuitsjoined to the flexible sheet by ribbon cabling for treatments requiringhigher power densities, higher dosing or treatment of specific areassuch as burns, infection or special anatomic areas such as oral gums.

It is yet another object of this invention to describe a system forwhich overcomes biological boundaries against diffusion by means of thesynergistic combination of multichannel iontophoresis and ultrasonicenhancement.

It is another object of the invention to provide a system for painless,controlled and safe delivery of drugs, peptide and other substancesthrough the skin or mucous membrane.

It is an advantage of the present invention that the iontophoreticmedicament applicator for large dermal areas improves the efficacy oftopical agents and reduces the risk of harmful side effects that mayoccur with oral systemic treatment techniques.

It is another advantage of the present invention that the disposableiontophoretic medicament applicator for difficult to treat areasconducts the electrical current to the tissue through the solution intowhich the medicament is dissolved.

It is still another advantage of the present invention that the improveddisposable iontophoretic medicament applicator has a low productioncost, is safe to use and increases the efficacy of the medicamentemployed.

It is another feature of this invention that this wide areaiontophoretic electrode is further enhanced by the adhesion of multipleultrasonic elements corresponding to each dispersion electrode channelto further enhance the applied and iontophoretically driven medicament.

It is still another feature of this combined system that the array ofultrasonic elements each generating (30 khz-60 khz) may be driven andenergized by circuitry in either serially, in parallel, or a combinationof each, or even in multiplex fashion depending on energy sources andlevel of miniaturization and portability.

It is still another feature that the ultrasonic field in lower energyapplications can be generated by incorporating a commercially availablepiezo film (i.e. Kynar PVDF film).

A preferred embodiment may be worn like a wide watch band with theelectronics and power source will be mounted thereon in a manner similarto a large watch. The inner surface of this band will contain the activeand grounding multichannel dispersive electrode. The ultrasonic elementsare to be placed within this band in close proximity to each electrodechannel. The inner surface may be an adhesive, an open cell material,insulin or other peptide-impregnatedhydrogel or other similar matrix.This inner band surface containing the medicament will be disposable andcontain a specified amount of desired medicament.

These and other objects, features and advantages are obtained by theimproved iontophoretic medicament applicator of the present invention.Various embodiments of the invention can be used to treat large dermalareas, localized areas or small and difficult to reach areas, and eveninclude a "watch band" type of a systemic drug delivery system.

This system readily lends itself to systemic delivery of medicationunder the control of a physiological sensor connected to the deliverysystem in a biofeedback configuration. Delivery of nitroglycerin basedon heart rate sensing; delivery of blood pressure medication based onblood pressure sensing; and ultimately, the transdermal delivery ofinsulin by means of the iontophoretic-ultrasonic system regulated andcontrolled by a similarly noninvasive glucose sensor.

BRIEF DESCRIPTION OF THE DRAWINGS

The objects, features and advantages of the invention will becomeapparent upon consideration of the following detailed disclosure of theinvention, especially when it is taken in conjunction with theaccompanying drawings wherein:

FIG. 1 is a top plan view of one embodiment of the improved multichanneliontophoretic applicator combined with several of the plurality ofultrasonic elements which can be used to treat large dermal areas.

FIG. 2 is a top, somewhat schematic, plan view of a miniaturizedembodiment of the improved iontophoretic-ultrasonic delivery systemcombined with a sensor (eg; tissue glucose, blood pressure, or heartrate sensors) to form a biofeedback system for intelligent andcontrolled drug delivery. This system can be worn as a "watch band" onan extremity.

FIG. 3 is a block circuit diagram of the iontophoretic-ultrasonic(ionosonic) medicament applicator's electrical control circuit used inconjunction with above applicators either as a separate power andcontrol unit or integrated into a single unit if market demand justifiesthe costs of such miniaturization.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

An ionosonic applicator electrode, generally indicated at the numeral10, is shown in FIG. 1. The applicator electrode 10 forms a closedcircuit through the patient's body when current is applied whichpromotes the penetration or absorption of an ionic medicament containedin a layer 18 of the working electrode 10. The polarity of the workingelectrode 10 is selected based upon the pelarity of the medicament to beadministered. The electrode 10 preferably comprises a flexible sheet orfilm forming a conductive matrix 15 having a current distributingconductive layer, such as a metallic foil, a conductive rubber or resinfilm, carbon film or other conductive coating or electro-dispersivematerial. The conductive matrix 15 is flexible so that it may becontoured to the body area on which it is placed and still cover arelatively wide area. Matrix 15 has a medicament carrying layer 18attached to it, such as by an adhesive. The medicament carrying layer 18is preferably formed from a porous material about 1/4 of an inch thickwhich can be a honeycombed sponge-like material with vertical cells tominimize cross flow or lateral dispersion of the medicament. Thegrounding electrode (not shown) employed with the multichannel electrode14 must also cover an-area similarly large in size to the area coveredby electrode 14.

A ribbon connector (not shown) connects an electrical power source (notshown) to the multichannel electrode 14 and delivers the electricalcurrent by means of the multiconnectors 19 to the lead wires 16 thatform the individual electrically conductive channels in the conductivematrix 15. Since the material of construction is flexible, the electrode10 may be folded over a rigid supporting substrate above the connectors19 to insure that a good electrical connection is made with the ribbonconnector. Each channel in the iontophoretic array 14 preferably carriesno more than 1 milliamps. The amount of current that flows to eachchannel is controlled by the control circuit (shown in FIG. 3) toprevent a tunneling effect from occurring. This prevents the flow ofcurrent along the path of least resistance through a lesion or skinrupture, for example, resulting in a burn to the patient at thatlocation. The multichannel electrode 14 can employ a circuit patternetched such as by laser or photoetching onto, for example, a metalcoated Mylar® plastic sheet with each channel isolated to facilitatedispersion over a broad surface area.

Each channel formed by the lead wires 16 can be electrically drivensimultaneously or in a sequential multiplex fashion. The use ofsimultaneous or parallel electrical current to each lead wire 16 in thearray 14 would be employed, for example, in the application ofmedicament to burns where a wide area of dispersion is required. Theiontosonic applicator greatly improves the skin penetration by themedicament to actively deliver the medicament to either a wide regionalarea or to a specific lesion.

Ultrasonic elements 11 made of piezoelectric crystal elements aremounted on this flexible electrode by means of a suitable adhesive suchas Silastic™ brand of silicone adhesive. Driving oscillator connections12 to the crystals can be photoetched onto a polymer sheet (eg;metalized Mylar™) with perforations on the sheet which facilitatemounting of the ultrasonic elements. This electrode can be effective inmoving Insulin across skin, as well as antibiotics, antifungal,anti-inflammatory, blood pressure medication and cardiotropic drugs;either as direct drive, logic control timer drive or more elegantly asbiofeedback control configuration. It is also effective in the treatmentof wide field dermatological conditions, such as eczema, psoriasis andacne. It is also effective for ionic retention of skin hydrating mediato facilitate skin hydration in cosmetic applications and in dermalexfoliation to drive medication into the skin in order to inflame theskin and cause the peeling of the external skin layer to stimulatereformation of collagen and collagen growth factors. The ionosonicapplicator may also prove useful for driving Minoxidil™ or relatedcompounds into the scalp to enhance hair growth and/or amelioratebaldness. The construction of ultrasonic elements can be piezo-electriccrystals, ceramics or distributed segments of Kynar™ PVDF piezo film.

The open-celled sponge-like material in the medicament carrying layer 18should be inert to the medicament or treatment agent being employed, aswell as being noncorrosive and stable. Suitable materials includeplastic pads, such as polyethylene, paper or cotton, porous ceramics,open-celled porous polytetrafluoro ethylene, other inert plastics, andopen-celled silicone rubber, preferably with vertically alignedmedicament-containing cells or tubes.

FIG. 3 shows a block circuit diagram of the iontophoretic medicatorelectrical control circuit suitable for use with the ionosonicapplicator of FIG. 1 and the miniaturized ionosonic applicatordiagrammed in FIG. 2. The control circuit, generally indicated at 30,may be either integrated with the electrode, as shown in FIG. 2, orboxed separately to drive the applicator electrode as shown in FIG. 1.The control circuit is equipped with a power source 31 which may beeither a battery or an isolated wall source.

The control box 30 is provided with a clock-operated timer switch 32 topreset the length of iontophoretic treatment mediated by the integralCPU. Once the length of time has been selected, a voltage multiplier isutilized to provide the current to iontophoretically drive themedicament into the patient's skin. The current is set and administereduntil the end of the treatment period. When the clock 32 signals the endof the treatment period, the electrical current to the electrode 10 isgradually terminated by a ramping down of the current to the patient toavoid abrupt change. Ribbon cable (not shown) provides a flexibleconnection to the multichannel neutral and active electrodes asindicated in FIG. 3, as well as delivering oscillator power for thepiezoelectric crystals 11 mounted on the applicator electrode 10.Internal circuit board controls allow for frequency adjustment,adjustment of maximum current per iontophoretic channel (not to exceed0.6 to 1.2 ma range),and internal control that will shut down anyiontophoretic channel electrically performing outside a "normal" rangeof encountered biological impedance.

FIG. 3 shows the block circuit diagram of the large area iontophoreticmedicator control circuit employed with the multichannel iontophoreticapplicator of FIG. 2. An isolated current loop generator is employed tofeed current to the individual channels in the multichannel electrodevia the plurality of individual current loops. Each current loop drivesone band or channel in the multichannel electrode. It has been foundthat 0.6 milliamps current flowing to each channel used within a widefield dispersion grounding electrode, such as that shown in FIG. 1,provides a safe level for operating the iontophoretic device. This levelof current avoids the tunnelling effect of current flowing along thepath of least resistance and concentrating in, for example, a lesion orskin rupture, resulting in a burn to the patient. This permits currentto be distributed over the large area of the multichannel electrode todrive medicament through a patient's skin over a large dermal area.Depending upon the electrode configuration, this current level can varyfrom about 0.1 to about 1.2 milliamps. The novel introduction ofdistributed ultrasonic piezoelectric elements combined with theiontophoretic multi electrodes described above greatly enhances the rateof penetration of many molecules. The use of ionosonic applications toadminister insulin transdermally now becomes feasible.

While the invention has been described above with references to specificembodiments thereof, it is apparent that many changes, modifications andvariations in the materials, arrangements of parts and steps can be madewithout departing from the inventive concept disclosed herein. Forexample, in employing the multichannel iontophoretic electrode of thepresent invention, it is possible to employ a biofeedback control of itsoperation to disperse, for example, more cardiovascular medicationduring periods of increased physiological demands, such as duringexercise or an angina attack, by linking the penetration ofnitroglycerine with heart rate; the physiological indicator of oxygendemand by the heart. In the latter instance, a sensor electrode wouldmeasure the increased demand and signal the controller 30 to stimulatemore delivery of the transdermal medication, in this case,nitroglycerine (commercially available under the trade name Nitropaste).This type of a biofeedback coupled with ionosonic application providesan active system for percutaneous nitroglycerine delivery which is animprovement over existing passive percutaneous delivery systems. Thepresent invention creates a further improvement in transdermalpenetration of medicament over prior purely iontophoretic deliverysystem by introducing ultrasonic drivers at the site of iontophoreticpenetration.

Alternate applications also exist in hormonal therapy, for example inthe administration of insulin or steroids based on blood sugar levelsand diurnal cycles, as appropriate. The large area multichannelelectrode shown in FIG. 1 can also be adapted for use in dentalanaesthesia in the form of a bite block, burn treatment and for thetreatment of baldness, such as by the transdermal administration ofMinoxidil®. Additionally, a conductive gel can also be used toimpregnate the porous medicament carrying medium to increase thephysical stability and the tissue adhering characteristics of theelectrode. Or, a medicament may be dispersed in conductive gel and alayer of the gel serve as the medicament carrying layer.

Accordingly, the spirit and broad scope of the appended claims isintended to embrace all such changes, modifications and variations thatmay occur to one of skill in the art upon a reading of the disclosure.All patent applications, patents and other publications cited herein areincorporated by reference in their entirety.

What is claimed:
 1. An ionosonic medicament applicator for use with amultichannel power source and adapted to be releasably attached to theskin of an organism for the transdermal delivery of medicament,comprising in combination:(a) a skin-contacting medicament containinglayer; (b) a multichannel iontophoresis electrode comprising at leastthree individual electrically isolated electrode channels, saidiontophoresis electrode overlying said medicament containing layer andeach of said individual electrically isolated electrode channels beingin electrical communication with said medicament container layer; and(c) an ultrasonic electrode overlying said medicament containing layerand comprising at least one piezoelectric element in mechanicalcommunication with said medicament containing layer, said at least onepiezoelectric element being operable for producing ultrasonic mechanicalvibrations in said skin-contacting medicament containing layer whenenergized by energizing means.
 2. The ionosonic medicament applicatoraccording to claim 1 wherein the medicament carrying layer comprises anopen-celled, absorbent porous material.
 3. The applicator according toclaim 2 wherein the open-celled, absorbent porous material is selectedfrom the group consisting of polyethylene, paper, cotton, silicone,polytetra-fluoroethylene and ceramic.
 4. A method for transdermallyadministering medicament to a patient comprising the steps of:(a)sensing a physiological indicator of the patient's condition; and (b)administering a dosed mount of medicament in response to the sensedphysiological indicator by means of an energized ionosonic applicator,which applicator comprises a skin-contacting medicament containinglayer, a multichannel iontophoresis electrode comprising at least threeindividual electrically isolated electrode channels, the iontophoresiselectrode overlying the medicament containing layer and each of theindividual electrically isolated electrode channels being in electricalcommunication with the medicament container layer, and an ultrasonicelectrode overlying the medicament containing layer and comprising atleast one piezoelectric element in mechanical communication with themedicament containing layer, the at least one piezoelectric elementbeing operable for producing ultrasonic mechanical vibrations in theskin-contacting medicament containing layer when energized by energizingmeans.
 5. The method according to claim 4 further comprising the stepsof:(a) repeating step (a) of claim 4 subsequent to the ionosonicadministration of the medicament in accordance with step (b) of claim 4;and (b) adjusting the dosed amount of medicament in response to thesensed physiological indicator and administering the adjusted dosedamount to the patient by means of control of energization of theionosonic applicator.
 6. An ionosonic medicament applicator for use witha multichannel power source and adapted to be releasably attached to theskin of an organism for the transdermal delivery of medicament,comprising in combination:(a) a skin-contacting medicament containinglayer; (b) a multichannel iontophoresis electrode comprising a pluralityof individual electrically isolated electrode channels, saidiontophoresis electrode overlying said medicament containing layer andeach of said individual electrically isolated electrode channels beingin electrical communication with said medicament container layer; and(c) an ultrasonic electrode overlying said medicament containing layerand comprising a plurality of discrete piezoelectric elements inmechanical communication with said medicament containing layer, saidpiezoelectric elements being operable for producing ultrasonicmechanical vibrations in said skin-contacting medicament containinglayer when energized by energizing means.
 7. The ionosonic medicamentapplicator according to claim 6 wherein the medicament containing layercomprises an open-celled, absorbent porous material.
 8. The applicatoraccording to claim 7 wherein the open-celled, absorbent porous materialis selected from the group consisting of polyethylene, paper, cotton,silicone, polytetra-fluoroethylene and ceramic.